N&#39; [nu-(monocarbocyclic aryl) carbamyllower-alkyl]-1, 5-iminocycloalkanes, -iminocycloalkenes and related compounds



United States Patent 3,264,309 N'[N-(MONOCARBOCYCLIC ARYL) CARBAMYL-LOWER-ALKYL] 1,5 lMINOCYCLOALKANES, -IMINOCYCLOALKENES AND RELATED COM-POUNDS Bernard L. Zenitz, Colonie, N.Y., assignor to Sterling Drug Inc.,New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 24,1959, Ser. No. 835,405 22 Claims. (Cl. 260292) This application is acontinuation-in-part of my prior copending application Serial No.697,531, filed November 20, 1957, now abandoned.

This invention relates to new monocarbocyclicarylcarbamyl-lower-alkylamines, to salts thereof, and to methods for thepreparation thereof.

N [N-(monocarbocyclic .aryl)carbamyl-lower-alkyl] amines andN'-[N-loWer-alkyl-N-(monocarbocyclic aryl) carbamyl-lower-alkyl]amineswherein the amino moiety is dialkylamino or piperidino are known. Theinvention resides in the concept of the compounds obtained when theknown types of N-(monocarbocyclic aryl)carbamyllower-alkyl andN-lower-alkyl-N-(monocarbocyclic aryl) carbamyl-lower-alkyl radicals areattached to the nitrogen atoms of a 1,5-iminocycloalkane or1,5-iminocycloalkene radical, whereby new and useful compounds areproduced.

In the compounds of my invention the monocarbocyclic aryl radicals canbe unsubstituted phenyl or phenyl substituted by substituents known incompounds of the lidocaine type having local anesthetic activity, suchas loweralkyl, lower-alkoxy or halogen.

In the compounds of my invention the 1,5-iminocycloaliphatic ring has atleast seven ring members, preferably seven or eight, and can beunsubstituted or substituted in the 3-position by such known types ofradicals as hydroxy, acyloxy, halogen, oxo, carboalkoxy, and the like.In the case where a 1,5-iminocycloalkene radical is present, the ringpreferably has the double bond at the 2,3-position of the ring.

A preferred aspect of the invention relates to compounds having theformulas:

wherein R, R' and R represent hydrogen, lower-alkyl, lower-alkoxy orhalogen radicals, R' represents hydrogen ice or a lower-alkyl radical, Yrepresents a lower-alkylene radical, n represents an integer from 1 to2, and A represents CH CH(OH), 0 0, CHCl, CHBr, CH(O-Acyl),C(OH)(COO-lower-alkyl) or C(OH)(lower-alkyl). The invention also relatesto salts of the foregoing.

In the above general Formulas I and II, R, R and R each representshydrogen, lower-alkyl, lower-alkoxy or halogen radicals and can be thesame ordifierent. When R, R and R represent lower-alkyl or lower-alkoxyradicals, they can have from one to about four carbon atoms and can bestraight or branched, and thus stand for such groups as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, butoxy,and the like. When R, R and R" represent halogen atoms, they stand forany of the four halogens, fluorine, chlorine, bromine or iodine. Aparticularly preferred class of compounds are those in which R and Rrepresent lower-alkyl radicals and R represents hydrogen.

In the above general Formulas I and II, R' represents hydrogen or alower-alkyl radical. When R represents a lower-alkyl radical, it canhave from one to four carbon atoms and can be straight or branched, andthus stands for such groups as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, Z-methylpropyl, and the like.

In the above general Formulas I and II, Y represents a lower-alkylenebridge having from one to about five carbon atoms which can be straightor branched, and thus includes such groups as methylene, ethylene,propylene, l-rnethylethylene, Z-methylethylene, butylene, penty-lene,and the like. A particularly preferred group of compounds are those inwhich Y has one or two carbon atoms, i.e., when Y is methylene orethylene.

In the above general Formula I, n is l or 2. When n is 1, the1,5-iminocycloalkane moiety is a cycloheptane ring, and the wholemolecule is a derivative of nortropane. When n is 2, the1,5-iminocycloalkane moiety is a cyclooctane ring, and the wholemolecule is a derivative of granatanine. The numbering systems are inaccordance with the standard nomenclature used in The Ring Index(Patterson and Capell, Reinhold Publishing Corp., 1940), and in ChemicalAbstracts. In the 1,5-iminocycloalkane or -alkene moiety theparenthetical numbers 8 and 9 are used in the case where n is 2.

In the above general Formula I, A represents, inter alia, a CH(O-Acyl)group. The exact nature of the acyl group is not critical, provided itis a carboxylic acyl group of relatively low molecular weight, less thanabout 250. A preferred group of acyl radicals includes lower-alkanoyl,such as formyl, acetyl, propionyl, butyryl, isobutyryl,

valeryl, caproyl, and the like; carboxy-lower-alkanoyl, such ashemi-succinyl, hemi-glutaryl, hemi-adipyl, and the like; monocarbocyclicaroyl, such as benzoyl, p-toluyl, pnitrobenzoyl, 3,4-dinitrobenzoyl,p-methoxybenzoyl, 3,4,5- trimethoxybenzoyl, and the like;monocarbocyclic aryllower-alkanoyl, such as phenylacetyl,2-.phenylpropionyl, l-phenylpropionyl, p -nitrophenylacetyl, and thelike; lower-alkanoyl, such as acryloyl, crotonoyl, and the like;monocarbocyclic aryl-lower-alkenoyl, such as cinnamoyl,p-nitrocinnamoyl, phenylcrotonoyl, and the like; and carbamyl, CONRR",wherein R' and R" are hydrogen or loWer-alkyl groups, such as carbamyl,N-methylcarbarnyl, N,N-dimethylcarbamyl, and the like.

The compounds of my invention have pharmacodynamic properties, inparticular, local anesthetic activity. For example, 8 [N (1,6dirnethyIphenyDcarbamYI- methyl]nortropaue as its hydrochloride salt wasfound .to. be, about 7.5 times as active as procaine hydrochlorideand 12.3 times as active as lidocaine hydrochloride when tested by the'intracutaneous wheal test in guinea pigs [Bulbring and Wajda, J.Pharmacol. & Exptl. Therap. 85, 78 r (1945)]. When tested by the cornealanesthesia method by topical application on the rabbit eye, thiscompound was found to be about 1.6 times as active as cocainehydrochloride;

The compounds of the invention are prepared by react-.

ing an N-(monocarbocyclic aryl) carbamyl lower alkyl halide or anN-lower-alkyl-N-(monocarbocyclic aryl)- carbamyl-lower-alkyl halide witha 1,5-iminocycloalkane or 1,5-iminocycloalkane. A preferred methodcomprises heating the reactants at .a temperature between about 50 C.and 150 C. in the presence of an acid-acceptor. The reaction ispreferably carried out in an organic solvent, inert under theconditions. of'the reaction, such :as

anhydrous lower-alkanols, benzene, xylene, and the like.

The acid-acceptor neutralizes the hydrogen halide which is split outduring the course of the reaction, and is a basic substance which formswater-soluble by-products easily separable from the main product ofthereaction, including such'substances asalkali metal salts of weak acids,e.g., sodium carbonate, potassium carbonate, sodium acetate, sodiumalkoxides, sodium amide, and the like. The acid-acceptor can also be inthe form of an excess quantity of 1,5-iminocycloalkane or -alkene, whichcan be recovered in the form of the hydrohalide salt and The hydroxycompounds can be dehydrated .to introduce a double bond between the 1-and 2-positions of the 1,5-

iminocycloalkane ring, e.g., by heating with mineral acid,

potassium bisulfate, or the like, and the double bond re-. duced to.give compounds unsubstituted in the .3-pos1t1on (A=CH Alternativelythehydroxygroup in the 3- position can be replaced by chlorine orbromine by treating with the thionyl chloride or'thionyl bromide, andthe resulting 3-chloro or '3-br'omo compound can then bedehydrohalogenated by heating with a base, such as alkali 1- metalhydroxides or alkoxides or amino compounds, to 4 give the sameunsaturated compound obtained by deh dration of the 3-hydroxy compound.

The compounds and intermediates wherein A is C=O 1 are converted tocompounds Where A is C(OH) (lower- -alkyl) by a Grignard reaction with alower-alkyl-lithium. Compounds wherein A is C=O also serves asintermediates for the compounds where A is C(OH)(COO-1oweralkyl);reaction with hydrogen cyanide gives the cyanhydrin [A=C(OH) (CN)] whichcan then be hydrolyzed ,to the corresponding carboxylic acid andesterified with a lower alkanol.

These changes in the groupA are preferably efiected before the1,5-iminocycloalkane and N-(monocarbocyclic aryl)carbamyl-lower-alkyl or"N-lower-alkyl N (monocarb o-cyolic aryl)-.carbamyl-lowcr-alky-lmoieties are oom-- bined in order to avoid side reactions with the amidelinkage. The foregoing is: summarized in the following 'floW-sheet (X isClor Br) l (base) My N'-[N-(monocarbocyclic 'aryl)carbamyl-lower-al-Ikyl]-amines and TN-[N-lower-alkyl N (monocarbocyclicaryl)carbamyl-lower-alkyl] amines are useful in the free base form or inthe; form of acid-addition or quaternary ammonium salts, and both formsare within the purview of the invention, and, in fact,"are considered tobe one and the: same invention; Th'e=acid-addition and quaternaryammonium salts are simply a more convenient form for use, andinapracticquseof' the salt form inherently amounts to use of the .baseform.., Asused in thea pended claims, unless specifically designated,otherwise, the terms N'-[N-(monocarbocyclic aryl) carbamyl-lowere alkyl]1,5. iminocycloalkane and -imin'ocycloalkene and N'--[N-loWer-alkyl-N-(monocarbocyclic aryl)car.- bamyl-lower-alkyl]1,5-iminocycloalkane? and -imino-- cycloalkene? mean ;both the free baseform and the acidaddition and-lower-alkyl, lower-alkenyl andmonocarbocyclic aryl-lower-alkyl quaternary ammonium salt form of themolecular structure recited. Pharmacologically acceptable salts are.salts whoseanions are innocuous to the animal organism inpharmacological doses of the salts,

so that beneficial physiological properties inherent in ;the V freebases-are not vitiated by side-effects ascribable to the anions; inother words, the latter do not substantially affect the pharmacologicalpropertiesinherent in the cations. Appropriate acids-addition saltsare-those derived from mineral acids such as hydrochloric acid,hydrobromic acid,:hydriodic acid, nitric acid, sulfuric acid,,andphosphoric acid; and organic acids such as acetic. acid, citric acid,lactic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid,'sulfamic acid and quinic acid andnaphthalenesulfonic acid. Thequa- I ternary ammonium salts are obtainedby the addition of alkyl, alkenyl or aralkyl esters of-in0rganic acidsor organic'sulfonic acids to the free base form of the compounds; The:alkyl, alkenyl or aralkyl esters so used include. such'cornpounds asmethyl chloride, methyl bro mide, methyl iodidegethylbromide, propylchloride, 2- hydroxyethyl bromide, allyl chloride, allyl bromide, methylsulfate, methyl benzenesulfonate', methyl p-toluenesulfonate, benzyl.chloride, benzyl bromide, and substituted benzyl halides, such asp-chlo'robenzyl chloride,

p-nitrobenzyl chloride, o-chlorobenzyl chloride, p-methoxy benzylchloride, and the like.

The acid-addition salts are prepared either by dissolving the free basein an aqueous solution containing the appropriate acid and isolating thesalt by evaporating the solution, or by reacting the free base and acidin an organic solvent, in which case the salt separates directly or canbe obtained by concentration of the solution.

The quaternary ammonium salts are prepared by mixing the free base andthe alkyl, alkenyl or aralkyl ester in an organic solvent. Heating canbe used to facilitate the reaction, although salt formation usuallytakes place readily at room temperature. The quaternary ammonium saltseparates directly or can be obtained by concentration of the solution.

An alternative method of preparation of the quaternary ammonium saltscomprises direct reaction of an N-(monocarbocyclicaryl)carbamyl-lower-alkyl halide or an N- lower alkyl-N-(monocarbocyclicaryl)carbamyl-loweralkyl halide with an N'-hydrocarbon substituted1,5-imir1o cycloalkane or -alkene.

Although pharmacologically acceptable salts are preferred, those havingtoxic anions are also useful. All acid-addition salts are useful asintermediates in purification of the free bases, and toxic acid-additionand quaternary ammonium salts are useful as intermediates in preparingpharmacologically acceptable salts by ion exchange procedures. Allcrystalline salts are also useful as characterizing derivatives of thefree bases.

The structures of the compounds of the invention have been establishedby chemical analysis and by the processes for their preparation, whichcan only lead to compounds of the assigned structures.

The following examples will further illustrate the invention, withoutthe latter being limited thereto.

EXAMPLE 1 8 N (2,6 dimethylphenyl)carbamylmethyl]-3-hydroxynortropane[1; R and R are CH R" and R'" are H, Y is CH n is 1, A is CH(OH)].Amixture of 9.9 g. (0.05 mole) of N (2,6 dimethylphenyl)carban1ylmethylchloride, 7.0 g. (0.055 mole) of nortropine and 5.3 g. (0.05 mole) ofpowdered anhydrous sodium carbonate in 150 ml. of absolute ethanol wasrefluxed with stirring for twenty-four hours. Another 2.7 g. of sodiumcarbonate was then added and the mixture refluxed for twenty-four hourslonger. The reaction mixture was filtered, the solid material washedwith ethanol, and the combined filtrate and washings were concentratedin vacuo. The residue was dissolved in 400 ml. of hot benzene, and thebenzene solution was washed several times with water and then extractedwith dilute hydrochloric acid. The acid extracts were made basic withconcentrated ammonium hydroxide and the precipitated product wascollected by filtration. The product was purified by dissolving it in250 ml. of hot benzene, concentrating the volume to 125 ml. and allowingthe product to crystallize. There was thus obtained 11.9 g. of8-[N-(2,6-dimethylphenyl)carbamylmethyl] 3 hydroxynortropane, M.P.177178.5 C. (corr.) after drying over phosphorus pentoxide at 100 C. and0.1 mm. for four hours.

Analysis.Calcd. for C17H24N2021 C, H, N, 9.72. Found: C, 70.78; H, 8.20;N, 9.67.

The hydrochloride salt of 8-[N-(2,6-dimethylphenyl)- carbamylrnethyl]-3-hydroxynortropane was prepared from a solution of 84 'g. of the freebase in isopropyl alcohol solution by addition of an excess ofconcentrated hydrochloric acid. The salt separated upon cooling thesolution, and there was obtained 89 g., M.P. 235-237 C. (corr.).

AnalysiS.Calcd. for C17Hz4N202.HCII N, Cl, 10.92. Found: N, 8.47; Cl,10.68.

The methiodide salt of 8-[N-(2,6-dimethylphenyl)- carbamylmethyl] -3-hydroxynortropane was prepared from a solution of 2 g. of the free baseand 4 g. of methyl iodide in 75 ml. of acetone. The solution was kept atroom temperature for three days, and the product which separated wascollected by filtration and washed with acetone, giving 2.4 g. ofmethiodide. A sample of the methiodide when recrystallized from ethanoland dried over phosphorus pentoxide at C. and 0.2 mm. for four hours hadthe M.P. 234237 C. (corr.).

Analysis.-Calcd. for C18H27N202I: N, I, 29.50. Found: N, 6.50; I, 29.59.

Pharmacological evaluation of 8-[N-(2,6-dimethylphenyl)carbamylmethyl] 3hydroxynortropane hydrochloride in aqueous solution administeredintradermally in guinea pigs according to the method of Bulbring andWa'jda [1. Pharmacol. & Exptl. Therap. 85, 78 (1945)] has shown thatthis compound in terms of its free base is approximately 2.4 times asactive a local anesthetic as procaine. 8- [N- (2,6-dimethylphenyl)carbamylmethyl] 3-hydroxynortropane hydrochloride was found to have anacute intravenous toxicity (LD in mice of 24:05 mg./kg.

By replacement in the preceding preparation of theN-(2,6-dimethylphenyl)carbamylmethyl chloride by a molar equivalentamount of N-phenylcarbamylmethyl chloride, N-(Z-methyl 6chlorophenyl)carbamylmethyl chloride,N-(2,4,6-trimethylphenyl)carbamylmethyl chloride,N-(2,4,6-triisopropylphenyl)carbamylmethyl chloride, orN-(2,6-dimethyl-4-n-butoxyphenyl)car'bamylmethyl chloride (prepared from2,6 dimethyl-4-n-butoxyaniline and chloroacetyl chloride), there can beobtained, respectively, 8-(N-phenylcarbamylmethyl) 3 hydroxynortropane[1; R, R, R and R are H, Y is CH n is 1, A is CH(OH)];8-[N-(2-methyl-6-chlorophenyl)carbamylmethyl]-3-hydroxynortropane [1; Ris CH R is Cl, R and R are H, Y is CH n is 1, A is CH(OH)];8-[N-(2,4,6-trimethylphenyl)carbamylmethyl] 3 hydroxynortropane [1; R, Rand R" are CH R" is H, Y is CH n is 1, A is CH(OH)];8-[N-(2,4,6-triisopropylphenyl)carbarnylmethyl] 3 hydroxynortropane [1;R, R and R are CH(CH R is H, Y is CH n is 1, A is CH(OH)]; or8-[N-(2,6-dimethyl-4-n-butoxyphenyl)carbamylmethyl]-3-hydroxynortropane[1; R and R are CH R is O(CH CH R" is H, Y is CH n is 1, A is CH(OH)].

By replacement in the preceding preparation of theN-(2,6-dimethylphenyl)carbamylmethyl chloride by a molar equivalentamount of 1-methyl-2-[N-(2,6-dimethylphenyl)carbamyl]ethyl chloride(prepared from 2,6-dimethylaniline and ,B-chlorobutyryl chloride) orS-[N- (2,6-dimethylphenyl)carbamyl1pentyl chloride (prepared from2,6-dimethylaniline and e-chlorocaproyl chloride), there can beobtained, respectively 8-{1-methyl-2-[N-(2,6-dimethylphenyl)canbamyl]ethyl} 3 hydroxynortropane [1; R and R areCH R and R are H, Y is CH CH(CH n is 1, A is CH(OH)]; or 8-{5-[N-(2,6-dimethylphenyl)carbamyl]pentyl} 3 hydroxynortropane [1; R and R are CH Rand R are H, Y is (CH n is l, A is CH(OH)].

By replacement in the preceding preparation of the nortropine by a molarequivalent amount of 3-granataninol there can be obtained9-[N-(2,6-dimethylphenyl) carbamylmethyl]-3-hydroxygranatanine [1; R andR are CH R" and R" are H, Y is CH n is 2, A is CH(OH)].

By replacement in the preceding preparation of the nortropine by a molarequivalent amount of 3-nortropanone, 3-chloronortropane (from nortropineand thionyl chloride), 3-bromonortropane (from nortropine and thionylbromide), 3-benzoyloxynortropane (from nortropine and benzoyl chloride),or 3-hydroxy-3-methylnortropane (from 3-nortropanone and methyllithium),there can be obtained, respectively, 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-oxonortropane [1; R and R are CH R and R" are H, Y isCH n is 1, A is C=O]; 8-[N- (2,6-dimethylphenyl)carbamylmethyl] 3chloronortropane [1; R and R are CH ,'R and R' are H, Y is .moved byfiltration and washed with benzene.

bine'd benzene filtrate and washings were washed with.

CH n is 1, A is CHCl];8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-bromonortropane [LR and RareCH R" and R are H, Y is CH n is 1, A is CHBr]; 8-[N-(2,6-dimethylphenyl)carbamylmethyl] 3 benzoyloxynortropane [1; R and Rare CH R" and R are H, Y is CH n-is 1,-A is CH(OCOC H )];;or 8-[N-(2,6-dimethylphenyl)carbamylmethyl] 3 hydroxy-3-methylnortropane [1; R and RareCH R and R are H, Y is CH n is LA is C(OH)(CH8-[N-(2,6-dimethylphenyl)carbamylmethyl] 3 hydroxynortropane. can bereacted with hydrochloric acid, hydrobromic acid, hydriodic acid,sulfuric acid, acetic acid, quinic acid, Z-naphthalenesulfonic acid,phosphoric: acid, methyl iodide, methyl bromide, ethyl bromide, allylbromide, benzyl chloride, .o-chlorobenzyl chloride, methylp-toluenesulfonate, or methyl sulfate, to give, respectively, thehydrochloride, hydrobromide, hydriodide, sulfate, or bisulfate, acetate,quinate, Z-naphthalenesulfonate, phosphate or acid phosphate,methiodide, methobromide; etho-.

bromide, allobromide, benzochloride, o-chlorobenzochloride,metho-p-toluenesu1fonate, or methosulfate. salt.

EXAMPLE 2 8 [N (2,6 dimethylphenyl)carbamylmethyl] nortropane [I;F=R andR are CH .R", and R are H, Y is CH n is 1, A is CH ].-A mixture of 5.9g. (0.030 mole) of N-(2,6-dimethylphenyl)carbamylmethyl chloride and i7.0 g. (0.063 mole) of nortropane in 150 ml. of dry benzene was refluxedfor eight hours. After the. T636. tion mixture had been allowed to standovernightythe white precipitate of nortropane. hydrochloride was re-.

two 50 ml. portions of water and extracted with dilute hydrochloric acid(4 ml. of concentrated hydrochloric acidin 50 ml. of water),-and washedwith water until neutral. made basic with ammonium hydroxide.

a volume of 300ml. There was thus obtained 7.2 g..of 8-[N-(2,-6dimethylphenyl) carbamylmethylJnortropane which was recrystallized from350 ml. of hexane. and dried.

over phosphorus pentoxide at 80 C. and 0.2 mm. for six hours, giving asample having the M.P. 154-155 C. (corn).

Analysis.-Calcd. for CHI-124N202 N (total), 10.29;

N (basic), 5.14. Found: N (total), 10.25; N (basic), 5.11.

The hydrochloride salt of 8-[N-(2,6-dimethylphenyl)-carbamylmethyHnortropane was prepared from a solution ,of 39 g. of thefree base in :200 ml. of isopropyl alcohol and 12.2 ml. of concentratedhydrochloric acid. Thetsolution was: filtered while hot'and then cooled,to 5 C. whereupon the product'separated. The salt was collected byfiltration, washed with cold isopropyl alcohol and dry ether, and driedat 70 C. for twenty hours, giving 40.5

pigs according to the method of Bulbring and Wajda, 10c. .cit., hasshown that this compound in terms of its freev base is approximately 7.5times as active a local anesthetic as procaine, and 2.3 times asactiveas lidocaine. '8-[N-' (2,6-dimethylphenyl)carbamylmethylJnortropane hydrochloride was found to have an acuteintravenous toxicity (LD in mice of.10.5 10.9 mg./kg.

EXAMPLE 3 I 8 [N (2,6.-dimethylphenyl)carbamylmethyl]nortropidz'ne [II;R and R are CH R" and R' areH, YiS CH n is .1] was prepared from 5.9 g.(0.030molc). of

The com-.

The acid extracts were combined, filtered, and The product was collectedby filtration, dissolved in 700 m1.- of hot: hexane and the solution wasfiltered and concentrated to.

8? N-(2,6,-dimethylphenyl)carbamylmethyl chloride and-6.9

g. (0.063 mole) of nortropidine in 150 m1. of dry benzene I to' have anacute intravenous toxicity. (LD in mice of 13:12 m g/kg.

EXAMPLEM 8 [N (2,6-dimethylphenyl)carbamylmelhyflpseudo-3-hydr0xyn0rtropane [1; R andR'. are CH R and R- are H, Y is CH n is 1,A is CH(OH)].-A mixture of 5.9. g. (0.030 mole) of N-(2,6-dimethylphenyl)carbamyl= methyl. chloride, 8.0g. (0.063 mole) ofpseudo-nortro-- pine in 100 ml. of absolute ethanol was refluxed foreight hours. The reaction mixture was allowed to stand overnight and.then.was concentrated in vacuo. was refluxed for several minutes"with-IOO-mhfiof chloroform, .cooled, and the insolublepseudo-nortropinehydrochloride ;was*removed :by filtration and i'washedwith chloroform. The combined chloroform filtrate and washings werewashed with three'25 ml. portions of water,

extracted with dilute hydrochloric acid (5 ml; of con centratedhydrochloric acid .in v50 ml. of water), and i The: combinedacidextracts and washings were filtered and. .made basic with: concentrated:ammonium hydroxide. The product whichseparated was collectedand1dissolved finally washed with four10 ml. portions of water.

in 200 fill-:Of benzene, and the solution was. filtered, concentrated toml. and. diluted with 30 m1..of hexane.

There was thus obtained 7.1 g. of8-[N(2,6-dimethylphenyl)carbamylmethyhpseudo 3 hydroxynortropanem whichwas further purified by recrystallization successively frombenzene-hexane, ethyl acetate-hexane and ethyl acetate, and dried overphosphorus pentoxidei atroom temperature and 0.1 mm. for twenty-fourhours to give a sample with the M.P. 176.5-1785 C. (corn). A mixedmelting point with the S-EN-(2,6-dimethylphenyl)carbamylmethyl]-3-hydroxynortropane obtained inExample 1 showed adepression to 149160 C.

Analysis.Calcd. ffor ci namo N (total), 9.72; N, (basic), 4.86. Found: N(total), 9.52; N (basic),.4.82.

Pharmacological evaluation of 8-[N-(2,6 -dimethylphenyl)carbamylmethyl]pseudo-3-hydroxynortropane in anaqueous solutionof its acid-addition salt'administered intradermally in guinea pigsaccordingto the method of Bulbring and Wajda, loc.- cit.., has shownthatthis com-- 1 pound in .terms of its free base is approximately 0.9times; as: active a local anesthetic as procain'e.. 8-[Nj-(2,6-di--methylphenyl)carbamylmethyl] pseudo 3 I- hydroxynop' tropanewas foundtov have an acuteintravenous toxicity )in mice of 581-4.8 mg./kg.

droxynortropane [1; R and R. are CH RT and R"! are H, Y-is CH CH n is 1,A is.CH(-OH)].A'rnixture of 12.7 g. (0.060 mole) of2-IN-(2,6-dimethylphenyl)care bamy1]ethy1'ch1oride,:8.0 g. (0.063 mole)of nortropine and 6.4 g; (0.06 mole) of anhydrous sodium carbonate in200 ml. of absolute ethanol was refluxed for twenty hours. The inorganicsolids .were removed by filtration,

The residue washed with ethanol, and the combined ethanol filtrate andwashings were concentrated in vacuo. The residue was dissolved in 200ml. of dilute acetic acid, the solution filtered through filter cel, andthen made basic with solid potassium carbonate. The mother liquors weredecanted from the resulting gum which was then washed with water anddissolved in chloroform. The chloroform solution was washed with 50 ml.of water, filtered, and concentrated in vacuo. The resulting pale yellowoil was dissolved in 150 ml. of boiling benzene, and the solution wasfiltered and concentrated to 75 ml. and diluted with 35 ml. of hexane,giving 10.6 g. of crystalline product, M.P. 117119 C. The latter wasrecrystallized twice from a benzene-hexane mixture and then twice fromethyl acetate and dried over phosphorus pentoxide at 100 C. and 0.05 mm.-for five hours giving 8-{2- [N-(2,6-dimethylphenyl) carb amyl]ethyl}-3ahydroxynortropane, M.P. 151-153" C. (corn).

Analysis.-Calcd. for C H N O N (total), 9.27; N (basic), 4.63. Found: N(total), 9.06; N (basic), 4.6 2.

Pharmacological evaluation of 8-{2-[ N(2,6-dimethylphenyl)carbamyl]ethyl}-3-hydroxynortropane in an aqueoussolution of its acid-addition salt administered intradermally in guineapigs according to the method of Bulbring and Wajda, loc. cit., has shownthat this compound in terms of its free base is approximately 1.2 timesas active a local anesthetic as procaine. 8-{2-[N- (2,6dimethylphenyl)carbamyl]ethvl}-3-hydroxynortropane was found to have anacute intravenous toxicity (LD in mice of 6810.4 trig/kg.

EXAMPLE 6 8 {2-[N-(2,6-dimethylphenyl)carbamyl]ethyl}n0rtr0- pane [1; Rand R are CH R and R are H, Y is OH CH n is 1, A is CH was prepared from8.5 g. (0.040 mole of N-(2,6-dimethylphenyl)carbamylethyl chloride, 4.7g. (0.042 mole) of nortropane and 4.2 g. (0.04 mole) of sodium carbonatein 200 ml. of absolute ethanol according to the manipulative proceduredescribed above in Example 5. There was thus obtained 9.9 g. of 8 {2[N-(2,6-dimethylphenyl)carb-amyl]ethyl}nortropane, M.P. 119-122 C.(corr.) when recrystallized from hexane.

Analysis.-Calcd. for C H N O: N (total), 9.78; N (basic), 4.89. Found: N(total), 9.73; N (basic), 4.85.

Pharmacological evaluation of8-{2-[N-(2,6-dimethylphenyl)carbamyl]ethyl}nortropane in an aqueoussolution of its acid-addition salt administered intradermally in guineapigs according to the method of Bulbring and Wajda, loc. cit., has shownthat this compound in terms of its free base is approximately 4 times asactive at local anesthetic as procaine. 8-{2-[N-(2,6-dimethylphenyl)carbamyl]ethyl}nortropane was found to have an acute intravenoustoxicity (LD in mice of 8.6 $0. 6 mgkg.

EXAMPLE 7 8-[N-(2,6-dimethylphenyl) carbamylmethyl] -3-acet0xynortropane [1; R and R are CH R and R are H, Y is CH n is 1, A isCHOCOCH ].A mixture of 4 g. of 8 [N(2,6-dimethylphenyl)carbamylmethyl]-3-hydroxynortropane (prepared asdescribed above in Example 1) and 4 ml. of acetic anhydride in 20 ml. ofpyridine was allowed to stand at room temperature overnight. Thereaction mixture was then heated on a steam bath for two hours andconcentrated in vacuo. The residue was dissolved in 25 ml. of absoluteethanol and the solution again concentrated in vacuo. The residue wasdissolved in 200 ml. of dilute acetic acid, and the solution filteredthrough filter cel and then made basic with potassium carbonate. Themixture was cooled and the product collected by filtration andrecrystallized from hexane, giving 4.1 g., M.P. l29l31 C. The latter wasrecrystallized from a mixture of 25 ml. of benzene and 50 ml. of hexane,and dried over phosphorus pentoxide 10 at C. and 0.3 for eight hours,giving 3.9 g. of 8- [N-(2-6-dimethylphenyl) carb amylmethyl]-3-acetoxynortropane, M.P. l42.5-144.5 C. (corn).

Analysis.-Calcd. for C19H26N203: C, H, N, 8.48. Found: C, 68.90; H,8.07; N, 8.32.

Pharmacological evaluation of8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-acetoxynortropane in anaqueous solution of its acid-addition salt administered intraderm'allyin guinea pigs according to the method of Bulbring and Wajda, loc. cit.,has shown that this compound in terms of its free base is approximatelyequally as active a local anesthetic as procaine.8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3 acetoxynortropane was foundto have an acute intravenous toxicity (LD in mice of 30:1.6 mg./kg.

By replacement in the preceding preparation of the acetic anhydride by amolar equivalent amount of cinnamoyl chloride, 3,4,5-trimethoxyben zoylchloride, N,N- dimethylcarb'almyl chloride, hexanoyl chloride, succinicanhydride, or phenylacetyl chloride, there can be obtained,respectively,8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-cinnamoyloxynortropane [1; Rand R are CH R and R are H, Y is CH n is 1, A is CHOCOCH CHC H J 8 [N(2,6-dimethylphenyl)carbamylmethyl]-3-trimethoxybenzoylnortropane [I; Rand R are CH R and R are H, Y is CH n is 1, A is CH0COC H (OCH 8[-N-(2,6-dimetlhylphenyl)carbamylmethyl]-3-dimethylcarbamyloxynortropane[I; R and R are CH R and R are H, Y is CH n is 1, A is OH-OCO N(CH 8[N-(2, 6-di=methylphenyl)carbarnylmethyl]3-hexanoyloxynortropane [I; Rand R are CH R and R are H, Y is 0H n is 1, A is CHOCO(OH OH3]; 8-[N-(2,6 dimethylphenyl)carbamylmethyl]-3-(B-carboxypropionyloxy)nortropane[1; R and R are CH R and R are H, Y is CH n is 1, A is CHOCOCH CH COOH];8 [N (2,6-dimethylphenyl)carbamylmethyl]-3-phenylacetoxynortropane I; Rand R are CH R and R are H, Y is 0H n is 1, A is CHOCOCH C H EXAMPLE 8 8[N-(2,6-dimethylphenyl)carbamylmethyl]-3-pr0pi0- nyloxynortropane I; Rand- R are CH R and R' are H, Y is CH n is 1, A is CHOCOC H was preparedfrom 5 g. of8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-hydroxynortropane and 5 g. ofpropionic anhydride in 25 ml. of pyridine according to the manipulativeprocedure described above in Example 7. This compound had the M.P.143144 C. (c'orr.) when recrystallized from a benzene-hexane mixture.

Analysis.Calcd. for CZdHggNgOgi C, 69.74; H, 8.19; N, 8.14. Found: C,69.84; H, 8.02; N, 7.91.

EXAMPLE 9 8 {2 [N (2,6-dimethylphenyl)carbamyl]ethyl}-3-acetoxynortropane [I; R and R are CH R" and R are H, Y is OH CH n is 1,A is CHOOOCH was prepared from 4 g. of 8-{2-[N-(2,6-di'methylphenyl)carbamyl]ethyl}-3-hydroxynortropane and 4 ml. ofacetic anhydride in 20 ml. of pyridine according to the manipulativeprocedure described above in Example 7. This compound had the M.P.119123 C. (corn) when recrystallized from a benzene-hexane mixture.

Analysis.Calcd. for C H N O C, 69.74; H, 8.19; N, 8.14. Found: C, 69.43;H, 8.46; N, 7.91.

Pharmacological evaluation of 8-{2-[N-(2,6-=dimethylphenyl)carbamyflethyl} 3 acetoxynontropane in an aqueous solution of itsacid-addition salt administered intradermally in guinea pigs accordingto the method of Bulbring and Wajda, loc. cit., has shown that thiscompound in terms of its free base is approximately 1.3 times as activea local anesthetic as procaine.

'1 1 EXAMPLE i 8[N-(2,6-dimethylphe'nyl)carbamylmethyl]-3-propionyloxynortropane [1; Rand R are CH R" and R are H, Y is CH CH n is '1, A is CHOCOC H wasprepared from 5 g. of 8-[N-(2,6-dimethylphenyl)-carbamylmethyl]3-hydroxynortr0pane and 5 g. of propionic anhydride in ml. of pyridineaccording to the manipulative procedure described above in Example 7.There was thus obtained propionyloxynortropane, MJP. 1094111 C. (corn)when recrystallized from hexane.

Analysis.-Calcd. for C H N O C, 70.35; H, 8.44;

N, 7.82 O, 13.39. Found: C, 70.58; H, 8.39; N,-7.63;-

.. EXAMPLE 11 (a) Nor-u-ecgonine methyl ester.-Northropinonehydrochlori-de (48.5 g, 0.30 mole) was added portionwise over a periodof fifteen minutes to. a solution of 21.5 g..

(0.33 mole) of potassium cyanide in 75 ml. of water.

The solid cyanhydrin which had separated was collected by filtration,washed with pyridine and dried over phosphorus pentoxide; Thecyanhydnin(56 g.) was added.

solved in about 100 ml. of water, decolo'rized with acti-' 'vatedcharcoal, and the solution was treated with;solid potassiumcarbonateuntil a white solid separated. The

mixture was extracted with three 100 ml. portions of'chloreform, and thechloroform solution was dried over .anhydrous calcium sulfate andconcentrated, .giving 22. 8 g. of solid product. The aqueous layer wasfurther saturated with potassium carbonate, and the solid which 'sepa-.rated was collected and washed with three 150 ml. portions ofchloroform.The chloroform washes were used to extract the aqueous filtrate, thendried andconcentrated, giving an additional 5.5 .g. of solid product.The combined solid product was recrystallized from 200 m1. of ethylacetate, giving 15.6 g. of nor-m-ecg-onine methyl ester, M.P. 143-145 C.

(b) 8 [N (2,6-dimethylphenyl)carbamylmethyl]-3-hydr0xy-3-carb0methoxynortropane [I; R and R are OH;;, R" and R.' are H,Y is CH n is 1, A is C(OH)@(OOO-CH A mixture of 5.7 g. (0.030 mole) ofN-(2,6-dimethylphenyDcarbamylmethyl chloride, 5.6 g. (0.030 mole) of Theresidue was washed with acetone and the.

nor-wecgonine methyl ester and 3.5 g. (0.033 mole) of EXAMPLE 12 '(a)Nortropi none ethylene glycol ketal.A mixture. of 48.5 g. (0.30 mole) ofnortropinone hydrochloride, 90 ml.

(1.5 moles) of ethylene glycol and 1 g. of p-toluenesulionic acidmonohydrate in 500 ml. ofdry benzenewas retfluxed tor nineteen hoursunder a water separator.

Th e' excess benzene and ethylene glycol were then removed in vacuo on asteam bath. The residue was stirred with ditional 11.9, g. of solidproduct.

product were combined and stirred with 75 ml. of satu-, rated potassiumcarbonate solution; chloroform was 1 added, the mixture was stirred andthe chloroform solu- 12 1 about 400 ml. ofdry acetone and filtered,giving 41.9 g. of. solid product. The filtrate was concentrated invacuo. to remove the acetone and additional ethylene glycol, and theresidue was agam treated with acetone to give anadtion-separated. Theaqueous mixture was filtered to .remove inonganic salts which werewashed with chloroform, and the combined chloroform extractsv andwashings were filtered through anhydrous calcium sulfate and concen- Theresidue was distilledthrough aa tratedin vacuo. Vigreuxcolumn, and thefraction boiling at,68-69. C.

(0.7-0.8 mm.) was collected and redistilled, giving 34.2 g.of'nortropinone ethylene glycol ketal, B.P. 70 C. (0.8 5.

(b) 8 [N (2,6-dimethylphenyl)carbamylmethyl] nortropinone ethyleneglycol ketal was prepared from 7.9 g. (0.040? mole) v ofN'-(*2,6-dimethylphenyl)carb-amyla methyl chloride, 7.4 g.: (0.044 mole)of nortropinone ethylene glycol ketalan-d 6.4 g. of anhydrous sodiumcar-7.

bonate in 200 ml. of, absolute; ethanol according to the col ketal,'M.P. 1267129" C.

Analysis-Calm. :for C H gN O3: C, 69.06; H, 7.94;

N, 8.48. Foundz C, 69.33; H,%8.08;'N,' 8.46.

(c) 8.- [N (2,6-dimethylphenyl)carbamylmethyl] nortropinone [-I; R andR-'are CH Rf and .R"! are H, Y is CH n is 1, A is C=O]:-A mixture of 2.4g. of 8-.[N-

(2,6- dimethylphenyl)! L- carbamylmethyl]nortropinone ethylene glycolketal, 2 ml. of concentratedhydrochloric acid and .15 ml. of waterwaskept at room temperature for about seventy hours The reaction mixturewas made basic vwith'saturatedpotassium carbonate, and the solidmaterial which separated was collected byfiltration and dissolved inchloroform. The chloroform solution was. (filtered through anhydrous,calcium sulfate and ;concen-= trated in vacuo. The: residue wasdissolved in .50 ml. of

boiling benzene, andthe solution.was filtered, concentrated to 25 ml.and diluted with ml. of hexane; The solution was cooled,,and theresulting product which separated was collected by :filtration,recrystallized from 25 ml. Otf benzene and 75 m1. of hexane and driedover phos-' phorus pentoxide at C. and 0.2 mm. for six hours,-

giving' 1.6 g. of 8-[N-( 2,6.-dimethylphenyl)oarbamyl.methyl[nortropinone,- M-.P.'204-205 C. (corn).

Analysis.Calcd. forC H N O C',7l.29; H, 7.74; N, 9.78. Found: C, 71.22;H, 8.05; N, 9.72. r

The oxime of 8-.[N-(2,6,-dimethylphenyl) car-bamylmethyl1nortropinone:was prepared by heating-4.3 g. of the ketone, 4 g. irof'hydroxylaminehydrochloride, 12 ml. of pyridine and 100 ml. of absolute ethanol at 100C. until a clear solution resulted- The reaction mixture was keptovernight at roomtemperature, refluxed'one hour,- and then concentratedin vacuo.. The residue was crystal: lized from water, giving 3.8 g.ofthe .oxime which had the MP. 1985-201 C.I(corr.) when recrystallizedfrom acetone- Analysis.'Calcd. for-C H N' O C, 67.74; H, 7.69; N, 13.94.Found: C; 67.50; H, 7.5.6;'N, 13.87

EXAMPLE l3 8- [N-ethyl-N v- (2,6-dimethylphenyl)carbamylmethyl]-3u-hydroxyrnortropane [I; R and R areCH ,;R'? is H, Ri'. is CgH Y is CHn is 1, A is CH(OH)].A solu-. tion of 14g. of chloroacetyl chloride in50 m1. of dry benzene was added dropwise over a one hourperiodto a lstirred solution of N-ethyl-2,6-dimethylaniline (14.9 g., 0.1 mole) in100 ml. of dry benzene while maintaining The two crops of's-olid thetemperature at 18 to 28 C. The mixture was then warmed on a steam bathfor about two and a half hours, cooled and diluted to 300 ml. withbenzene. The solution was extracted once with dilute hydrochloric acid,three times with water and twice with saturated sodium bicarbonatesolution. The organic layer was dried, filtered, and taken to dryness invacuo. The residual oil was taken into hot hexane, charcoaled andfiltered. On cooling, the product separated as large crystals which werecollected and dried giving N-ethyl-N-(2,6-dimethylphenyl)carbamylmethylchloride, M.P. 4143 C. (uncorn).

Analysis.-Calcd. for C H NCIO: N, 6.22. Found: N, 6.22.

The N-ethyl-N (2,6-dimethy1phenyl)carbamylmethyl chloride (6.76 g., 0.03mole) and nortropine (8.01 g., 0.063 mole) in 250 ml. of acetonitrilewere refluxed for about 18 hours. The reaction mixture was worked upaccording to the procedure described above in Example 2. There was thusobtained 3.76 g. of 8-[N-ethyl-N-(2,6- dimethylphenyl)carbamylmethyl] 3ahydroxynortropane, M.P. 95.298.4 C. (corr.).

Ananlysis.-Calcd. for C H N O N (basic), 4.43; N

(total), 8.86. Found: N (basic), 4.41; N (total), 8.87.

By replacement in the preceding preparation of the N-ethyl-N-(2,6-dimethylphenyl)carbamylmethyl chloride by a molarequivalent amount of2-[N-ethyl-N-(2,6-dimethyl-4-isopropylphenyl)-carbamyl]ethyl chloride,N-butyl- N-(2-chloro-6-methylphenyl) carbamylmethyl chloride, orN-isopropyl N (2,6-dirnethylphenyl)carbamylmethyl chloride, there can beobtained, respectively, 84 2-[N- ethyl-N-(2,6-dimethyl 4isopropylphenyl)carbamyl] ethyl}-3-hydroxynortropa11e [1; R and R are CHR" is CH(CH R' is C H Y is CH CH n is 1, A is CH(OH); 8-[N-butyl N(2-chloro-6-rnethylphenyl)- carbamylmethyl] -'3-hydroxynortropane [1; Ris CH R is Cl, R" is H, R is C H Y is CH n is 1, A is CH(OH) or 8-[N-isopropyl-N- (2,6-dimethylphenyl)carbarnylmethyl]-3-hydroxynortropane [I; R and R are CH R is H, R' isCH(CH Y is CH n is 1', A is CH(OH)].

By replacement in the preceding preparation of the nortropane by a molarequivalent amount of 3-nortropanone, 3-chloronortropane (from nortropineand thionyl chloride), 3-bromonortropane (from nortropine and thionylbromide), 3-benzoyloxynortropane (from nortropane and benzoyl chloride),3-hydroxy-3-methylnortropane, nortropane, nortropidine orS-granataninol, there can be obtained, respectively,8-[N-ethyl-N-(2,6-dimeth ylphenyl)-carbamylmethyl]-3-oxonortropane [I; Rand .R' are CH R is H, R is C H Y is CH n is 1, A is C=O]; S-[N-ethyl N(2,6-dimethylphenyl)carbarnylmethyl] 3-chloronortropane [1; R and R areCH R Y is CH m is 1, A is CHCl]; S-[N- ethyl-N-(2,6 dimethylphenyl)carbamylmethyl1-3-bromonortropane [I; R and R are CH R is H, R is C H Yis CH n is 1, A is CHBr]; 8-[N-ethyl-N-(2,6-dimethyl-phenyl)carbamylmethyl] 3-benzoyloxynortropane [I; R and R are CH R is H, R is CH Y is CH n is 1, A is CH(OCOC H8-[N-ethyl-N-(2,6-dimethylphenyl)carbamylmethyl]-3-hydroxy3-methylnortropane [I; R and R are CH R is H, R is C H Y is CH n is 1, Ais C(CH )(OH)];8-[N-ethyl-N-(2,6-dimethylphenyl)carbamylmethyl]nortropane [1; R and Rare CH R is H, R is C H Y is CH n is 1, A is CH 8 [Nethyl-N-(2,6-dimethylphenyl)carbamylmethyl]nortropidine [II; R and R areCH R is H, R is C H Y is CH n is 1];9-[N-ethyl-N-(2,6-dimethylphenyl)carbamylmethyl] 3 hydroxygranatanine[1; R and R are CH R is H, R is C H Y is CH n is 2, A is CH(OH)].

EXAMPLE 14 8-[N-pr0pyl N (2,6dimethylphenyl)carbamylmethyl]-3-hydroxynortropane [1; R and R are CH Ris H, R is (CH CH Y is CH n is 1, A is CHOH].-

14 N-propyl-Z,6-dimethylaniline (16.3 g., 0.1 mole) in 150 ml. of drybenzene was treated with a solution of 15.0 g. (0.13 mole) ofchloroacetyl chloride in 600 ml. of dry benzene according to themanipulative procedure described above in Example 13. The product wasrecrystallized from hexane giving 20.1 g. of N-propyl-N-(2,6-dimethylphenyl)carbamylmethyl chloride, M.P. 5960 C. (uncorr.).

Analysis.Calcd. for C H NClO: N, 5.84; Cl, 14.80. Found: N, 5.92; Cl,15.00.

N-propyl N (2,6-dirnethylphenyl)carbamylmethyl chloride (7.19 g., 0.03mole) and 8.01 g. (0.063 mole) of nortropine in 250 ml. of acetonitrilewere reacted according to the manipulative procedure described above inExample 2. The product was isolated in the form of the free base andrecrystallized from dry benzene giving 4.56 g. of 8- [N-propyl-N-(2,6-dimethylphenyl) carbamylmethyl1- 3-hydroxynortropane, M.P.1l9.6-121.0 C. (corr.).

Analysis.Calcd. for C2oH3 N2O2: N (total), 8.49; N (basic), 4.25. Found:N (total), 8.39; N (basic), 4.17.

EXAMPLE 15 1-{ 8-[N methyl N-(2,6-dimethylphenyl)carbamyl]ethyl}-3-hydr0xynortropane hydrochloride [I; R, R and R are CH R is H, Yis CHCH n is 1, A is CHOH].--A solution of 26.0 g. (0.12 mole) ofozbromopropionyl bromide in 60 ml. of dry benzene was added dropwisewith stirring and cooling to a solution of 13.5 g. (0.10 mole) ofN-methyl-2,6-dimethylaniline in 120 ml. of dry benzene according to themanipulative procedure described above in Example 13. The product wasrecrystallized from hexane giving 17.1 g. of l-[N- methyl-N(2,6-dirnethylphenyl)carbamylethyl1bromide, M.P. 80.5 C. (uncorr.).

Analysis.-Calcd. for C H BrNOz C, 53.34; H, 5.97; Br, 29.6. Found: C,53.29; H, 5.77; Br, 29.4.

The 1-[N-methyl-N-(2,6 dimethylphenyl)carbamylethyl]-bromide (8.1 g.,0.03 mole), nortropirie (4.2 g., 0.033 mole) and sodium bicarbonate (7.5g., 0.09 mole) in ml. of acetonitrile were refluxed for 72 hours. Thereaction mixture was worked up according to the procedure describedabove in Example 1. The product was isolated in the form of thehydrochloride salt and recrystallized from an isopropanol-acetonemixture giving 1.3 g. of 1% S-[N-methyl N-(2,6-dimethylphenyl)carbamyuethyl} 3 hydroxynortropane hydrochloride, M. P. 250.0-2512" C.(dec.) (corr.).

Analysis.-Calcd. for C H N O -HC1: C, 64.66; H, 8.28; N, 7.94. Found: C,64.88; H, 8.54; N, 7.91.

EXAMPLE l6 8- [N-methyl N-(2,6-dimethylphenyl)carbamylmethyl] nortropane[1; R, R and R are CH R is H, Y is CH n is 1, A is CH].N-methyl-2,6-dimethylaniline (9.6 g., 0.064 mole) was treated with 15ml. of chloroacetyl chloride in dry toluene according to themanipulative procedure described above in Example 13. The product wasrecrystallized from pentane giving 10.8 g. of N-methyl-N-(2,6dimethylphenyl)carbamylmethyl chloride, M.P. 4143 C. (uncorr.).

N-methyl-N- (2,6-dimethylphenyl carbamylmethyl chloride (6.35 g., 0.03mole) was treated with 7.01 g. (0.063 mole) of nortropane in 250 ml. ofacetonitrile according to the manipulative procedure described above inExample 2. The product was isolated as the free base and recrystallizedfrom hexane giving 4.08 g. of S-[N-methyl- N-(2,6-dimethylphenyl)carbamylmethyl]nortropane, M.P. 82.6-86.6 C. (corr.).

Analysis.Calcd. for C H N O: C, 75.50; H, 9.15; N,

9.78. Found: C, 76.46; 'H, 9.25; N, 9.85.

of its free base is approximately as active as a local anesthetic asprocaine.

EXAMPLE 17 8 [N ethyl N (2,6 dimethylphenyl)carbamylmethyl]nrtr0pane [I;R and R are CH R" is H, R is C H Y is CH n is 1, A is CH].N-ethyl-N-(2,6,-di methylphenyl)carbamylmethyl chloride (6.76 g., 0.03mole) was reacted with 7.01 g. (0.063 mole) of nortropane in 250 ml.ofacetonitrile according to the manipulative procedure described abovein Example 2. The product Was isolated in the form of the free .base andrecrystallizedfrom hexane giving 5.10 g. of B-[N-ethyl-N-(2,6-dimethylphenyl)carbamylmethyl]nortropane, M.P.

81.6-83.4 C. -(corr.).

Analysis.Calcd. for C T-1 N 05 N (total), 9.48; N

(basic), 4.66. Found: N (total), 9.48; N. (basic), 4.60.

Pharmacological evaluation of8-[N-ethyl-N-(2,6-dimethylphenyl)'carbamylmethylJnortropane in anaqueous solution of its acid addition salt administered intradermah lyin guinea pigs according to the method of Bulbring and Wajda, loc. cit.,has shown that this compound in terms of its free base is approximately2.3 times as active a local anesthetic as procaine.

EXAMPLE 18 8 [N propyl N (2,6 dimethylphenyl)carbamylmethyl1nortropanehydrochloride [1; R and R. are CH R is H, R' is (CH CH Y is CH n is 1, Ais CH N-propyl N (2,6-dimethylphenyl) carbamylrnethyl chloride (7.19 g.,0.03 mole) was reacted with 7.01 g. (0.063

mole) of nortropane in 260 ml. of acetonitrileaccording to themanipulative procedure described above in Example 2. The product wasisolated in the formof its hydro,- chloride salt and recrystallized froman ethanol-ether mixture giving 4.57 g. of 8-[N-propyl-N-(2,6-dimetl1ylphenyl) carbamylmethyl]nortropane.hydrochloride, M.P. 142 .-6-. 143.6 C. (c'orr.).

Analysis.Calcd. for CQ H N Q'HCI: N, 7.98; Cl,

10.10. Found: N, 8.04; Cl, 10.28-

The intermediate N-lower-alkyl-substituted-anilines used in thepreparation'of the N-lower-alkyl-N-(monocarbocyclicaryl)carbamyl-lower-alkyl halides are prepared by re-.

ducing the correspondiug N-lower-alkanoyl-substitutedanilineswith analkali metal aluminum hydride, for ex-' ample, lithium aluminum hydride,in an organic solvent;

N-ethyl-2,6-dimethylaniline, B.P. 9395 C./ 15 mm.,

n 1.5225,v prepared from N-acetyl-2,-6-dimethylaniline. Analysis.Calcd.for C H N: N, 9.38; Found; N,

N-propyl-2,6-dimethy1aniline, B.P. 115.5-118.5 c./24

mm., n 1.5177, prepared from -N propionyl-2,6-dimeth-' 'ylaniline.

Analysis.-Calcd. for C H N: N, 8.57. Found: N,

; Local anesthetic compositions can be formulated using the novelN'-[N-(monocarbocyclic a-ryl)carbamyl-loweralkyl] 1,5-iminocycloa1kanesand -all:enes and their salts disclosed herein together with excipients.By an excipient.

I mean any inert substance used to give the compositions a'suitable formor consistency. In the case of liquid compositions for topical or.injectable administration, the ex-' cipientvis sterile water,optionally containing additional,

compatible ingredients for stabilizing and the like purposes such asmethyl para-hydroxybenzoate, chlorobutanol, sodium bisulfite, sodiumchloride, dextrose, inositol, etc., 75 C(OH) (COO lower-alkyl), andC(OH) (lower-alkyl);

or containingother pharmacodynamically active ingredients such asa.vasoconstrictor agent,1e.g., epinephrine, phenylephrine; In the caseof ointment or cream compositions for topical application, theexcipient=is prefer ably petrolatum, optionally containingadditionalcompatible ingredients such as lanolin, mineral oil, whitewax,

wool fat, etc... Illustrative of suchlocal anesthetic compositions of myinvention are thefollowing: an injectable aqueous preparation comprisingin reach cubic centimeter 10 mg. of 8-[N-(2,6-dimethylphenyl)carbamylmethyl] nortropane. hydrochloride, 7 mg.ofzsodiumchloride and 1 mg. of methyl para-hydroxybenzoate; aninjectafble aqueous preparation comprising inieach cubic centimeter 20mg. of 8-[N-(2,6-dimethylphenyl)carbamylrnethyflnorr tropanehydrochloride, 0.01 mg. 'of'epinephrine 'hydrochloride, 6 mg. of sodiumchloride andl mg. of methyl para-hydroxybenzoate; a topical. aqueous'composition comprising 10. mg. of 8-[N-(2,6-dimethylphenyl)carbam-:ylmethylJnortropane hydrochloride, 4 mg.. of. ChlOIObll-s itanol andenough distilled Water to make 1 ml. of solu tion; an ointmentcomprising, 1% of 8-'[N-(2,6-'dimethy1-'phenyl)carbamylmethyllnortropane dissolved tin. white petrolaturn.

I claim:

pounds having the formula I (oHiu-oH-om and compounds having theiormulal (GHzh-CHCH where R and R, ,each' are .a member of the group:consistingmof lower-alkyl, lower-alkoxy, and .halogen; ,R" is a memberof the group consisting of hydrogen, loweralkyl, lower-alkoxy, andhalogen; .R".' is a memberof-the group ,consisting of hydrogenandlower-alkyl, Y is loweralkylene, n is an integer from 1 to 2, and Ais'a member of the group consisting of CH OH(OH), C=.O, CHCl, CHBr;'CHCOAcyI) wherein Acyl -is a carboxylic acyl group conventionallyusedin the. tropine alkaloid art and having a molecular weightless thanabout 250,. C(OH)%v (COO-loWer-alkyl) and .C(OH) (lower-alkyl) e (B)pharmacologically acceptable acid-addition salts thereofland '(C)pharmacologically.acceptable lower-alkyl, lower-- alkeuyl andmonocarbocyclic aryl-lower-alkyl. quaternary ammonium salts thereof.

25A memberyof the.group;consisting1of (A) compoundshaving the formula:

" r R OH2$11&H2

and compoundshaving the formula where R7, is a memberof the groupconsisting of hydro-' 1. A'member of the group. consisting of (A) com--17 and (B) pharmacologically acceptable acid-addition salts thereof.

3. A pharmacologically acceptable acid-addition salt of a compoundhaving the formula wherein R and R represent lower-alkyl radicals, Yrepresents a lower-alkylene radical, and n represents the integer l. v

4. A pharmacologically acceptable acid-addition salt of a compoundhaving the formula wherein R and R represent lower-alkyl radicals, Yrepresents a lower-alkylene radical, and n represents the integer 2.

5. A pharmacologically acceptable acid-addition salt of a compoundhaving the formula wherein R, R and R' represent lower-alkylradicals, Yrepresents a lower-alkylene radical, and n represents the integerll.

6. A pharmacologically acceptable acid-addition salt of a compoundhaving the formula wherein R and R represent lower-alky-l radicals, Yrepresents a lower-alkylene radical, n represents the integer 1, andAcyl represents a carboxylic acyl group conventionally used in thetropine alkaloid art and having a molecular weight less than about 250.

7. A pharmacologically acceptable acid-addition salt of a compoundhaving the formula wherein R and R' represent lower-alkyl radicals, Yrepresents a lower-alkylene radical, n represents the integer 2, andAcyl represents a car-boxylic acyl group conventionally used in thetropine alkaloid art and having a molecular weight less than about 250.

8. A pharmacologically acceptable acid-addition salt of a compoundhaving the formula wherein R and R represent lower-alkyl radicals, Yrepresents a lower'alkylene radical, and n represents the integer 1.

t v t 18 9. A pharmacologically acceptable acid-addition salt of acompound having the formula wherein R and R represent lower-alkylradicals, Y represents a lower-alkylene radical, and n represents theinteger 2.

10. Apharmacologically acceptable acid-addition salt of a compoundhaving the formula (CH2) n-OH-Cl-Iz wherein R, R and R representlower-alkyl radicals, Y represents a lower-alkylene radical, and nrepresents the integer 1.

11. A pharmacologically acceptable acid-addition salt of a compoundhaving the formula wherein R and R' represent lower-alkyl radicals, Yrepresents a lower-alkylene radical, and n represents the integer 1.

12. A pharmacologically acceptable acid-addition salt of a compoundhaving the formula wherein R and R represent lower-alkyl radicals, Yrepresents a loWer-alkylene radical, and n represents the integer 2.

13. A pharmacologically acceptable acid-addition salt of a compoundhaving the formula I @WOMILII wherein R and R represent lower-alkylradicals, Y represents a lower-alkylene radical, and n represents theinteger 1.

14. A pharmacologically acceptable acid-addition salt of a compoundhaving the formula 18. A pharmacologically acceptable acid-addition saltof 8-[N-(2,6 dimethylphenyl)carbamylmethyl] 3 ace- 5 t ttoxynortropane.

19. A pharmacologically' acceptable acid-addition salt of 8- [N (2,6dimet'hylphenyl)carbamylmethyl] nortropane.

- 20. 8- [N- 2,6-dimethylphe'nyl) car-bamylmethyl] n0rtro-.

pane hydrochloride.

21. A pharmacologically' acceptable acid-addition salt of 8- [N (2,6dimethylphenyl)carbamylmethyflnortrm pidine.

22. A pharmacologically acceptable acid-addition salt of 8[N'- (2,6dimethylphenyl)carbamylmcthyl] -no1'-uecgonine methyl ester.

20 R'eferencesCited-by the Examiner, 1

UNITED STATES PATENTS 2,824,106 1 52/1958 Zei'le-et al 260-12922,872,452 2/1959 Zeile 26O''292 2,891,064 6/1959 Kundiger- .260-'2932,921,075 1/1960 Shapiro et a1. 260292 WALTER A. MODANCE, PrimaryExaminer.

IRVING MARCUSQHERBERT' J. 'LIDOFF, JOHN D;

RANDOLPHgZExuminem.

D. T. 'MCCUTCHENJ. M-. FORD, Assistant Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N003,264,309 August 2, 1966 Bernard Lo Zenitz It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 3, line 2, for [1, 6-" read M (2,6-

line 16, for "1,S-iminocyc1oa1kane" read 1,5-iminocyc1oalkene column 9,line 37, for "mole" read mole) column 10, line 46, for "CH n read M CH ncolumn 11, line 17, for "Northropinone" read M Nortropinone column 13,line 23, for "Ananlysis" read Analysis D Signed and sealed this 22nd dayof August 1967c (SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A MEMBER OF THE GROUP CONSISTING OF (A) COMPOUNDS HAVING THE FORMUULA2. A MEMBER OF THE GROUP CONSISTING OF (A) COMPOUNDS HAVING THE FORMULA: